This invention relates to an improved process for the production of phenyl amino alcohols. In a particular aspect, this invention relates to a method for selectively preparing the erythro and the threo isomers of diastereomeric phenylamino alcohols.
Phenylamino alcohols are widely used pharmaceuticals for vaso-constrictor activity, appetite suppressants and the like. Most of those in use contain an asymmetric carbon atom and exhibit optical activity. Many of the more useful ones, e.g. 2-amino-1-phenyl-1-propanol (phenylpropanolamine), have a second asymmetric carbon atom and also exist as diastereoisomers, namely the threo and erythro forms.
The threo and erythro forms generally produce different pharmacological responses. The threo form of racemic 2-amino-1-phenyl-1-propanol is active as an appetite suppressant but relatively weak as a vaso-constrictor. On the contrary, the erythro form (Propadrine) exhibits powerful vasoconstrictor activity. Accordingly, it has long been the practice to separate the diastereoisomers of such compounds when possible, though it is usually difficult and costly to do so, or to prepare the preferred isomer by a process which produces it exclusively.
Mixed isomers of 2-amino-1-phenyl-1-propanol can be readily prepared by reacting benzaldehyde with nitroethane in the presence of an alkaline catalyst to produce 2-nitro-1-phenyl-1-propanol and reducing the nitro group, as is known from F. W. Hoover and H. B. Hass, J. Org. Chem. 12, 506 (1947). This reaction gives excellent yields at low cost, but the mixture of isomers cannot be resolved satisfactorily to provide the erythro isomer in good yield. In fact, four recrystallizations were needed to prepare the erythro isomer of the hydrochloride of 2-amino-1-phenyl-1-propanol and they described the yield as "low".
Commercially, racemic, erythro 2-amino-1-phenyl-1-propanol (Propadrine) is usually prepared by reacting propiophenone with an alkyl nitrite to produce isonitrosopropiophenone which is reduced catalytically to the erythro isomer of the amine. This procedure, although satisfactory, is quite expensive. A need, therefore, exists for an improved process for selectively preparing erythro and threo isomers of diastereomeric phenylamino alcohols.